Role of the novel presynaptic protein PRRT2 in neuronal physiology and in the pathogenesis of paroxysmal neurological disorders

Epilepsy, paroxysmal dyskinesia and hemiplegic migraine have a strong genetic component and a number of associated genes are likely to be uncovered. The variable phenotypic spectrum ranges from mild forms that improve and eventually disappear with age to severe phenotypes. The latter ones definitely need new and specific therapeutic approaches. The goal of this project is to assess the impact of an unknown protein, PRRT2, whose mutations have been recently associated with an astonishing number of the above paroxysmal diseases and to clarify the mechanisms that lead to these variety of diseases by using neuronal cells in which the expression of the protein has been enhanced or inhibited, as well as induced pluripotent stem cells generated from fibroblasts of patients with paradigmatic cases of the PRRT2-associated diseases. The role of this protein is completely unknown, although its synaptic localization and association with SNAP-25, a protein involved in neurotransmitter release, indicate a physiological function in the regulation of synaptic transmission. While the paroxysmal nature of the attacks, together with the association with epilepsy and migraine, suggest the presence of an increase of excitability in brain circuits, the variable phenotypes associated with PRRT2 mutations may reflect the existence of multiple targets of this protein with distinct functional roles. The elucidation of the functional role of the protein and of its dysfunctions could represent a step forward for the identification of new therapeutic solutions and allow the design of targeted therapeutic strategies for pathological phenotype of patients bearing mutations of the PPRT2 gene.